Targeting Lipid Metabolism in Colorectal Cancer

项目总结 转移是包括结直肠癌(CRC)在内的实体瘤的主要死亡原因。我们的长期合作 目标是开发更具选择性的治疗方案，通过以下方式预防或减少结直肠癌转移 了解脂肪酸代谢的变化如何导致转移性疾病。 脂肪酸合成酶(FASN)是从头合成脂质的关键酶，显著上调和 在结直肠癌中被激活，其活性与预后不良、疾病复发和死亡的风险较高有关。 我们确定FASN是晚期结直肠癌的潜在靶点，并表明该酶的上调是一种 支持结直肠癌转移的关键机制。然而，FASN调节的潜在机制是 转移和抵抗FASN抑制的潜在机制尚不清楚。当前应用程序 提出一项全面的研究计划，以研究脂质调节结直肠癌转移的新机制 新陈代谢。我们的初步数据表明，从头合成脂肪酸的主要产物棕榈酸酯是 选择性地用于神经鞘脂的合成。FASN的过表达选择性调节SphK1和SphK1的活性 SphK2，并增加鞘氨醇-1-磷酸(S1P)的水平，S1P是一种与 转移。因此，在目标1中，我们将检验FASN通过上调FASN的 SphK/S1P轴，我们将确定SphK1和SphK2在结直肠癌转移中的作用。此外，我们的 初步研究表明FASN的表达与脂肪酸转位酶CD36之间存在相关性 负责外源FA的吸收。我们的数据显示，抑制FASN导致CD36和CD36上调 这可能是对目前正在进行阶段测试的新型FASN抑制剂产生耐药性的潜在机制 II临床试验。因此，在目标2中，我们将阐明FASN如何调节CD36并确定分子 CD36上调促进结直肠癌转移的机制包括CD36的作用 上调鞘脂代谢和S1P合成。在目标3中，我们将测试抑制FA摄取 VIA CD36将提高新型FASN抑制剂TVB-3664治疗结直肠癌的疗效。 我们将利用患者的生物样本，人类原代结直肠癌细胞，从 转基因小鼠和结直肠癌转移模型，这是临床前最先进的模型 靶向和药物评估。这些模型将与最先进的方法结合使用，包括 靶向稳定同位素分解代谢组学(SIRM)评价脂质合成改变的影响 以及FA摄取对癌细胞代谢的影响。这些研究具有很高的翻译影响，因为CD36和FASN 目前，抑制剂正在多个临床前研究和I-II期临床试验中进行测试，迫切需要 以获得更多关于它们在儿童权利公约中的影响的研究和知识。除FASN、SphKs和CD36 AS验证外 结直肠癌的治疗靶点，代谢和信号通路的综合分析 目前的应用也有可能确定结直肠癌的新的可用药靶点和治疗策略。

PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). Our long-term goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by understanding how changes in fatty acid metabolism contribute to metastatic disease. Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated and activated in CRC, and its activity is associated with poor prognosis, higher risk of disease recurrence, and death. We identified FASN as a potential target for advanced CRC and showed that upregulation of this enzyme is a key mechanism supporting metastasis in CRC. However, the underlying mechanisms of FASN regulation of metastasis and potential mechanism of resistance to FASN inhibition are not understood. The current application proposes a comprehensive research plan to study novel mechanisms of regulation of CRC metastasis by lipid metabolism. Our preliminary data suggest that the primary product of de novo fatty acid synthesis, palmitate, is selectively used for sphingolipid synthesis. Overexpression of FASN selectively regulates activity of SphK1 and SphK2 and increases the level of sphingosine-1-phosphate (S1P), a bioactive sphingolipid implicated in metastasis. Therefore, in Aim 1, we will test the hypothesis that FASN enhances metastasis by upregulating the SphK/S1P axis and we will determine the contributions of SphK1 and SphK2 to CRC metastasis. Furthermore, our preliminary studies show a correlation between expression of FASN and CD36, a fatty acid translocase responsible for exogenous FA uptake. Our data show that inhibition of FASN leads to upregulation of CD36 and it can be a potential mechanism of resistance to novel FASN inhibitors that are currently being tested in Phase II clinical trials. Therefore, in Aim 2, we will elucidate how FASN regulates CD36 and determine molecular mechanisms by which upregulation of CD36 contributes to CRC metastasis including the effect of CD36 upregulation on sphingolipid metabolism and S1P synthesis. In Aim 3, we will test whether inhibition of FA uptake via CD36 will increase efficacy of a novel FASN inhibitor TVB-3664 in CRC. We will utilize biological samples from patients, human primary CRC cells, tumor organoids established from genetically modified mice and CRC metastasis models, which are the most advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with state-of-the-art approaches, including targeted and stable isotope-resolved metabolomics (SIRM), to evaluate the effect of alteration in lipid synthesis and FA uptake on cancer cell metabolism. These studies have a high translational impact since CD36 and FASN inhibitors are currently tested in multiple pre-clinical studies and Phase I-II clinical trials and there is urgent need for more research and knowledge on their effects in CRC. Beside validation of FASN, SphKs and CD36 as therapeutic targets in CRC, the comprehensive analysis of metabolic and signaling pathways proposed in the current application also have the potential to identify new druggable targets and therapeutic strategies for CRC.